High Response Rate With First Targeted Drug for Bladder Cancer

More details about the first targeted therapy for bladder cancer have now been published, and they show the response rate to be even higher than previously reported.

The novel agent, erdafitinib (Balversa, Janssen) was granted accelerated approval by the US Food and Drug Administration (FDA) in April. Erdafitinib is an inhibitor of fibroblast growth factor receptor (FGFR).

The approved indication was used in patients with locally advanced or metastatic bladder cancer and FGFR3 or FGFR2 genetic alterations that have progressed following treatment with platinum-based chemotherapy.

The agency added that patients must be selected for therapy with a newly approved companion diagnostic device, the therascreen® FGFR RGQ RT-PCR Kit (Qiagen Manchester).

Approximately 20% of patients with advanced urothelial carcinoma have FGFR alterations, which tend to act as a driver mutation in most of these cases.

At the time, the FDA said that the "approval represents the first personalized treatment targeting susceptible FGFR genetic alterations for patients with metastatic bladder cancer."

When it announced the approval, the agency noted that erdafitinib showed an overall response rate (ORR) of 32.3%.

Now the full results of the phase 2 clinical trial on which that approval was based have been published in the New England Journal of Medicine.

They show that the ORR was 40% in all of the patients who were treated, and that three patients achieved a complete response.

In addition, in a subgroup of patients who had previously received immunotherapy, the ORR was 59%.

"The results are quite promising, especially if you compare it to checkpoint inhibitors, where the response rate is about 20%," said principal investigator Arlene Siefker-Radtke, MD, professor of genitourinary medical oncology at the University of Texas MD Anderson Cancer Center in Houston. "We also saw an excellent response in patients with poor kidney function and visceral metastases, and these patients tend to do poorly with immunotherapy.

"Erdafitinib has been approved in the second-line setting," Siefker-Radtke told Medscape Medical News. "This is important because there are very few options for these patients and there is a definite unmet need."

An expert approached for independent comment agreed. Matthew R. Zibelman, MD, assistant professor in the Department of Hematology/Oncology at the Fox Chase Cancer Center in Philadelphia, Pennsylvania, said this is a welcome addition for patients and provides a viable treatment option for a sizable subset of the metastatic urothelial population.

"All patients with metastatic urothelial carcinoma should have their tumor tested for FGFR mutations, much like how we test for EGFR in all lung cancer patients," he told Medscape Medical News.

"At this time, the place for this drug is after patients have experienced progression on prior platinum-based and immunotherapy options, but it may be considered earlier in those contraindicated to get those prior therapies," he added.

High Response Rate

Patients with locally advanced and unresectable or metastatic urothelial carcinoma have historically received single-agent chemotherapy with taxanes or vinflunine in the second-line setting, which typically resulted in an ORR of only about 10%, note the authors.

The advent of new agents such as immune checkpoint inhibitors has improved the response rates (13 to 21%), and has also improved survival, although it remains quite low.

Erdafitinib has shown antitumor activity in preclinical models with a variety of solid tumors and in a phase 1 study that included patients with urothelial carcinoma and FGFR alterations.

The newly published results come from a multicenter, open-label, phase 2 study (BLC2001) conducted in 99 patients with locally advanced and unresectable or metastatic urothelial carcinoma with FGFR alterations.

All patients had experienced disease progression during or after at least one course of chemotherapy or within 12 months after neoadjuvant or adjuvant chemotherapy, and prior immunotherapy was allowed.

Patients were initially randomly assigned to receive erdafitinib in either an intermittent or a continuous regimen in the dose-selection phase of the study. On the basis of an interim analysis, the starting dose was set at 8 mg per day in a continuous regimen. This included a provision for a pharmacodynamically guided dose escalation to 9 mg.

The study's primary endpoint was the ORR, while key secondary endpoints included progression-free survival, duration of response, and overall survival.

The confirmed response rate was 40%, according to investigator assessment, and the median time until the first assessment of a confirmed response was 1.4 months.

Among the 74 patients with FGFR mutations only (no FGFR fusions), the ORR was 49%.

There were three complete responses, 37 partial responses, 39 patients achieved stable disease, 18 progressed, and 2 could not be evaluated.

A subset of 22 patients had previously been treated with immunotherapy, and the confirmed response rate for this group was 59%. Only 1 patient in this group had a history of responding to previous immunotherapy.

When looking at secondary endpoints, the median duration of response was 5.6 months and about 30% of responses were maintained for more than 12 months. Among the 39 patients with stable disease, 13 (33%) had disease stabilization for more than 6 months.

At a median follow-up of 11.2 months, the median progression-free survival was 5.5 months, and at 12 months, the rate of progression-free survival was 19%.

At a median follow-up of 11.0 months, the median duration of overall survival was 13.8 months; the rate of overall survival at 12 month follow-up was 55%.

All patients experienced adverse events (AE) during treatment, and grade 3 or higher treatment-related AEs were reported in 46% of the patients. These were managed primarily by dose adjustments, but 13% of the patients discontinued treatment because of adverse events. The most common high-grade events included hyponatremia (11%), stomatitis (10%), and asthenia (7%), and there were no treatment-related deaths.

Works Even When Immunotherapy Doesn't?

A phase 3 trial is ongoing to evaluate the efficacy of erdafitinib as compared with chemotherapy or immunotherapy with pembrolizumab (Keytruda, Merck) in patients with metastatic urothelial cancer and FGFR3 mutations.

"It will be comparing them head to head, and [will] assess if the mutation confers a benefit," Siefker-Radtke commented. "There is also a phase 1 study that is evaluating erdafitinib combined with a checkpoint inhibitor."

The current findings suggested that patients with FGFR mutations or fusions may be less likely to respond to immunotherapy, she noted. The phase 1 study will evaluate if the response to immunotherapy can be enhanced with the addition of erdafitinib, she added.

In his comments to Medscape Medical News, Zibelman pointed out an intriguing finding from this study: out of 22 patients that had prior immunotherapy, only 1 had a response to immunotherapy, but 59% of those patients had a response to erdafitinib.

"This suggests that patients with FGFR mutations may be more likely to be resistant to immunotherapy," he said. "However, I would caution that this is a small group and at this time is only hypothesis-generating. Thus, I would not forgo potential durable disease control with checkpoint inhibition in FGFR-mutated metastatic urothelial carcinomas, but I would have a low threshold to stop immunotherapy at first signs of progression to switch to erdafitinib in eligible patients."

Erdaftinib was approved on the basis of this phase 2 trial and on the basis of surrogate endpoints, and it is still unknown whether it confers an overall survival benefit. There has been harsh criticism of the FDA for approving drugs on the basis of such evidence, with some commentators arguing that the agency should wait until data on the hard endpoint of survival are available.

However, Zibelman points out that the agency has been accepting of data other than survival for biomarker-targeted or rare tumors where no standard of care exists .

"Since there is no clear alternative option for these patients, no drug that is known to improve overall survival and a strong signal of efficacy in a biomarker-selected population, I think approval of erdafitinib was reasonable," he said.

"I have already treated some of my patients with erdafitinib, and would advocate for all patients with metastatic urothelial cancers to undergo next-generation sequencing, and for clinicians to strongly consider this drug or relevant FGFR-targeting trials for eligible patients."

The study was funded by Janssen Research & Development, LLC. Siefker-Radtke serves on the scientific advisory committee for Janssen. Zibelman has disclosed no relevant financial relationships.

N Engl J Med. Published online July 25, 2019. Abstract

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